The ultimate goal of this Program Project Grant competiting renewal application is to elucidate mechanisms of retrovirus-mediated disease or cellular control events that regulate lymphocyte proliferation/ transformation. A primary common thread among all research groups is the shared use of infectious molecular clones and derivatives of human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2, developed or characterized in our laboratories, and links to established animal models (HIS mice, transgenic mice, rabbits) to test molecular determinants of disease. Each Project Leader brings a unique Project that is interdependent on components of other Projects and Cores in the Program. Project 1 (Green) in collaboration with Project 4 (Ratner) will identify cellular interacting components of both Hbz RNA and protein and will use in vitro and in vivo models to determine the interplay between Hbz and Tax to uncover the mechanisms and pathways necessary for tumor initiation, promotion or maintenance. Project 2 (Kvaratskhelia) in collaboration with Project 1 (Green) and Project 4 (Ratner) will investigate the molecular mechanisms and roles of HTLV-1 integration site selectivity for proviral expression, cell transformation and ultimately pathogenesis. Project 3 (Weilbaecher and Rosol) combines their expertise with Projects 1, 2, and 4 to test the hypothesis that dysregulated tumoral expression of bone turnover factors in Tax and Hbz expressing tumors will reprogram the ATL bone microenvironment towards increased osteoclast resorption and decreased bone formation, which will favor tumor expansion in bone. Project 4 (Ratner) in collaboration with Project 1 will identify and characterize Tax-interactive proteins to determine the mechanism of action of alternative NF?B activation and determine the role of this pathway in Tax-mediated transformation. These four highly integrated Projects are supported by three unique shared resource cores: Core A (Administration and Biostatistics), Core B (Proteomics and Protein Analysis) and Core C (Animal Model Use and Development). For the past 5 years, investigators within this PPG realized robust productivity as demonstrated by 77 peer-reviewed manuscripts; 43% collaborative between PPG investigators. This competing renewal PPG assembles and integrates a unique team of physician scientists, basic scientists, lab animal veterinarians, and pathologists and will support interactive basic and translational studies to define transformation mechanisms and therapeutic intervention against HTLV-1 associated leukemia/lymphomas and other related cancers.